The pathogenesis of late-life depression and antidepressant therapeutic response may involve postmenopausal estrogen deficiency. Existing data suggest that estrogen replacement therapy (ERT) in postmenopause enhances both mood-related symptoms and cognitive function. No data exit on the relationship between ERT and central serotonergic systems (5-HT). Further, no placebo-controlled trials evaluating the specific effects or ERT on clinical response to antidepressant treatment have been undertaken. The proposed research will: 1) evaluate 5-HT and cognitive functions in postmenopausal depressed women (PDW) compared with body-mass and age-matched postmenopausal controls (PC); and 2) assess antidepressant treatment outcomes for PDW. This project will use pharmacological challenge with fenfluramine for an assessment of 5-HT function in 40 postmenopausal women with major depression and 40 non- depressed controls, ages 45 to 65. A cognitive test battery will be used to assess cognitive function in PDW and PC subjects prior to and after the treatment phase. Impact of ERT on cognition will be assessed in double-blind placebo controlled trial: 1) in PC assessing efficacy of ERT vs. placebo, and 2), on cognition and mood outcomes in PDW assessing the efficacy of ERT plus antidepressant vs. antidepressant alone. This research will be the foundation for a future investigation of pathophysiology of reproductive-related mood disorders.